The use of drugs for the purpose of producing a particular physiological response is well known in the medicinal arts. Drugs are defined herein as any biologically-active chemical or natural substances useful for treating a medical or veterinary disorder, preventing a medical or veterinary disorder, or regulating the physiology of a human being or animal. There are a number of limitations to the potential therapeutic benefits derived from the clinical use of drugs, including the ability of the drug to elicit an immune response in the circulatory system.
The immune response involves the production of antibodies to the drugs by the circulatory system. This antibody production may decrease or eliminate the desired biological function of the drug, sometimes by causing reduced residence time in the circulatory system (reduced circulatory half-life) or by virtue of the antibody-drug interaction. Circulatory half-life of peptide drugs may also be reduced due to the ability of proteases to readily cleave peptide bonds.
The problems of immunogenicity and short circulatory half-life are well known and various modifications to drugs have been used in attempts to solve them. These include the modification of proteins with substantially straight chain polymers such as polyethylene glycol (PEG) or polypropylene glycol (PPG). There are numerous patents and publications which describe these modification attempts which are represented by Davis et al., U.S. Pat. No. 4,179,337; Katre et al., International Publication No. WO 87/00056, and Katre et al., European Publication No. EP0247860. However, previous modification attempts have used only monofunctional or difunctional polymers. The present invention differs from these prior modifications in that the polymers are trifunctional or greater and that the modification chemistry is through an isocyanate.
U.S. Pat. No. 4,094,744 (Hartdegan) discloses an aqueous solution of protein bound to an isocyanate-capped urethane polymer. However, the Hartdegan solution is prepared under essentially anhydrous conditions and it has been found that chain extension occurs to yield small amounts of insoluble material which is separated by filtration. The preferred methods used to prepare the solution of the present invention are performed under aqueous conditions and do not yield insoluble material. Hartdegan also specifies a linear polyoxyalkylene polyurethane backbone.
The prior art methods of modification do not teach how to use biocompatible isocyanate-capped high molecular weight triols or higher polyols to greatly decrease the immunogenicity of a drug and increase circulating half-life. The present invention offers a unique method of modifying drugs which accomplishes these goals.